rs375607980

Positions:

• chr11-47349875-T-A
• chr11-47349875-T-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000256.3(MYBPC3):​c.553A>T​(p.Lys185Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYBPC3 NM_000256.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 6.20

Genes affected

MYBPC3 (HGNC:7551): (myosin binding protein C3) MYBPC3 encodes the cardiac isoform of myosin-binding protein C. Myosin-binding protein C is a myosin-associated protein found in the cross-bridge-bearing zone (C region) of A bands in striated muscle. MYBPC3 is expressed exclusively in heart muscle and is a key regulator of cardiac contraction. Mutations in this gene are a frequent cause of familial hypertrophic cardiomyopathy. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-47349875-T-A is Pathogenic according to our data. Variant chr11-47349875-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 181044.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-47349875-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYBPC3	NM_000256.3	c.553A>T	p.Lys185Ter	stop_gained	5/35	ENST00000545968.6	NP_000247.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYBPC3	ENST00000545968.6	c.553A>T	p.Lys185Ter	stop_gained	5/35	5	NM_000256.3	ENSP00000442795	P4
MYBPC3	ENST00000399249.6	c.553A>T	p.Lys185Ter	stop_gained	5/34	5		ENSP00000382193	A2
MYBPC3	ENST00000544791.1	c.553A>T	p.Lys185Ter	stop_gained, NMD_transcript_variant	5/27	5		ENSP00000444259

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 21, 2017	The Lys185Stop variant in the MYBPC3 gene has not been reported as a disease-causing variant or as benign polymorphism to our knowledge. Lys185Stop is predicted to cause loss of normal protein function either by protein truncation or nonsense-mediated mRNA decay. Other nonsense variants in the MYBPC3 gene have been reported in association with HCM. In summary, Lys185Stop in the MYBPC3 gene is interpreted as a disease-causing variant. Variants in the MYBPC3 gene have been reported in 20%-30% of patients with autosomal dominant familial hypertrophic cardiomyopathy, and have been reported less frequently in patients with autosomal dominant familial dilated cardiomyopathy (Cirino A et al., 2011; Hershberger R et al., 2009). In summary, Gly5Arg in the MYBPC3 gene is interpreted as a disease-causing variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Cardiomyopathy Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Feb 13, 2020

- -

Hypertrophic cardiomyopathy 4 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

May 26, 2020

Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 Loss-of-function is a known mechanism of disease for this gene. Premature termination variants have previously been reported in this gene (ClinVar). (N) 0108 This gene is known to be associated with both recessive and dominant disease (OMIM). (N) 0201 Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (exon 5 of 35). (P) 0251 Variant is heterozygous. (N) 0301 Variant is absent from gnomAD. (P) 0701 Comparable variants have very strong previous evidence for pathogenicity. Multiple NMD-predicted variants have previously been reported pathogenic (ClinVar). (P) 0802 Moderate previous evidence of pathogenicity in unrelated individuals. This variant has previously been reported in clinical cases (ClinVar; PMID 27483260). (P) 0905 No segregation evidence has been identified for this variant. (N) 1007 No published functional evidence has been identified for this variant. (N) 1208 Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign -

Hypertrophic cardiomyopathy Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 19, 2021

For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with hypertrophic cardiomyopathy (HCM) (PMID: 27483260). ClinVar contains an entry for this variant (Variation ID: 181044). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Lys185*) in the MYBPC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MYBPC3 are known to be pathogenic (PMID: 19574547). -

Cardiovascular phenotype Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 01, 2024

The p.K185* pathogenic mutation (also known as c.553A>T), located in coding exon 5 of the MYBPC3 gene, results from an A to T substitution at nucleotide position 553. This changes the amino acid from a lysine to a stop codon within coding exon 5. This variant was reported in an individual with features consistent with hypertrophic cardiomyopathy (Rubattu S et al. Int J Mol Sci, 2016 Jul;17). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.65
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.80
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.97	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.88
GERP RS		4.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs375607980; hg19: chr11-47371426;